Are the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers?

Aung Ko Win; John L. Hopper; Daniel D. Buchanan; Joanne P. Young; Albert Tenesa; James G. Dowty; Graham G. Giles; Jack Goldblatt; Ingrid Winship; Alex Boussioutas; Graeme P. Young; Susan Parry; John A. Baron; David Duggan; Steven Gallinger; Polly A. Newcomb; Robert W. Haile; Loïc Le Marchand; Noralane M. Lindor; Mark A. Jenkins

doi:10.1016/j.ejca.2013.01.029

Are the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers?

Aung Ko Win, John L. Hopper, Daniel D. Buchanan, Joanne P. Young, Albert Tenesa, James G. Dowty, Graham G. Giles, Jack Goldblatt, Ingrid Winship, Alex Boussioutas, Graeme P. Young, Susan Parry, John A. Baron, David Duggan, Steven Gallinger, Polly A. Newcomb, Robert W. Haile, Loïc Le Marchand, Noralane M. Lindor, Mark A. Jenkins

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

Background: Genome-wide association studies have identified at least 15 independent common genetic variants associated with colorectal cancer (CRC) risk. The aim of this study was to investigate whether 11 of these variants are associated with CRC risk for carriers of germline mutations in DNA mismatch repair (MMR) genes. Methods: A total of 927 MMR gene mutation carriers (360 MLH1, 442 MSH2, 85 MSH6 and 40 PMS2) from 315 families enrolled in the Colon Cancer Family Registry, were genotyped for the single nucleotide polymorphisms (SNPs): rs16892766 (8q23.3), rs6983267 (8q24.21), rs719725 (9p24), rs10795668 (10p14), rs3802842 (11q23.1), rs4444235 (14q22.2), rs4779584 (15q13.3), rs9929218 (16q22.1), rs4939827 (18q21.1), rs10411210 (19q13.1) and rs961253 (20p12.3). We used a weighted Cox regression to estimate CRC risk for homozygous and heterozygous carriers of the risk allele compared with homozygous non-carriers as well as for an additive per allele model (on the log scale). Results: Over a total of 40,978 person-years observation, 426 (46%) carriers were diagnosed with CRC at a mean age of 44.3 years. For all carriers combined, we found no evidence of an association between CRC risk and the total number of risk alleles (hazard ratio [HR] per risk allele = 0.97, 95% confidence interval [CI] = 0.88-1.07, p = 0.52). Conclusions: We found no evidence that the SNPs associated with CRC in the general population are modifiers of the risk for MMR gene mutation carriers overall, and therefore any evidence of proven clinical utility in Lynch syndrome.

Original language	English (US)
Pages (from-to)	1578-1587
Number of pages	10
Journal	European Journal of Cancer
Volume	49
Issue number	7
DOIs	https://doi.org/10.1016/j.ejca.2013.01.029
State	Published - May 2013

Keywords

Colorectal cancer
Genetic variant
Lynch syndrome
Mismatch repair

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1016/j.ejca.2013.01.029

Cite this

Win, A. K., Hopper, J. L., Buchanan, D. D., Young, J. P., Tenesa, A., Dowty, J. G., Giles, G. G., Goldblatt, J., Winship, I., Boussioutas, A., Young, G. P., Parry, S., Baron, J. A., Duggan, D., Gallinger, S., Newcomb, P. A., Haile, R. W., Marchand, L. L., Lindor, N. M., & Jenkins, M. A. (2013). Are the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers? European Journal of Cancer, 49(7), 1578-1587. https://doi.org/10.1016/j.ejca.2013.01.029

Win, AK, Hopper, JL, Buchanan, DD, Young, JP, Tenesa, A, Dowty, JG, Giles, GG, Goldblatt, J, Winship, I, Boussioutas, A, Young, GP, Parry, S, Baron, JA, Duggan, D, Gallinger, S, Newcomb, PA, Haile, RW, Marchand, LL, Lindor, NM & Jenkins, MA 2013, 'Are the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers?', European Journal of Cancer, vol. 49, no. 7, pp. 1578-1587. https://doi.org/10.1016/j.ejca.2013.01.029

@article{3480272d21f34bc987a071ef62474db4,

title = "Are the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers?",

abstract = "Background: Genome-wide association studies have identified at least 15 independent common genetic variants associated with colorectal cancer (CRC) risk. The aim of this study was to investigate whether 11 of these variants are associated with CRC risk for carriers of germline mutations in DNA mismatch repair (MMR) genes. Methods: A total of 927 MMR gene mutation carriers (360 MLH1, 442 MSH2, 85 MSH6 and 40 PMS2) from 315 families enrolled in the Colon Cancer Family Registry, were genotyped for the single nucleotide polymorphisms (SNPs): rs16892766 (8q23.3), rs6983267 (8q24.21), rs719725 (9p24), rs10795668 (10p14), rs3802842 (11q23.1), rs4444235 (14q22.2), rs4779584 (15q13.3), rs9929218 (16q22.1), rs4939827 (18q21.1), rs10411210 (19q13.1) and rs961253 (20p12.3). We used a weighted Cox regression to estimate CRC risk for homozygous and heterozygous carriers of the risk allele compared with homozygous non-carriers as well as for an additive per allele model (on the log scale). Results: Over a total of 40,978 person-years observation, 426 (46%) carriers were diagnosed with CRC at a mean age of 44.3 years. For all carriers combined, we found no evidence of an association between CRC risk and the total number of risk alleles (hazard ratio [HR] per risk allele = 0.97, 95% confidence interval [CI] = 0.88-1.07, p = 0.52). Conclusions: We found no evidence that the SNPs associated with CRC in the general population are modifiers of the risk for MMR gene mutation carriers overall, and therefore any evidence of proven clinical utility in Lynch syndrome.",

keywords = "Colorectal cancer, Genetic variant, Lynch syndrome, Mismatch repair",

author = "Win, {Aung Ko} and Hopper, {John L.} and Buchanan, {Daniel D.} and Young, {Joanne P.} and Albert Tenesa and Dowty, {James G.} and Giles, {Graham G.} and Jack Goldblatt and Ingrid Winship and Alex Boussioutas and Young, {Graeme P.} and Susan Parry and Baron, {John A.} and David Duggan and Steven Gallinger and Newcomb, {Polly A.} and Haile, {Robert W.} and Marchand, {Lo{\"i}c Le} and Lindor, {Noralane M.} and Jenkins, {Mark A.}",

note = "Funding Information: This work was supported by the National Cancer Institute, National Institutes of Health under RFA #CA-95-011 and through cooperative agreements with members of the Colon Cancer Family Registry and Principal Investigators. Collaborating centres include Australasian Colorectal Cancer Family Registry (U01 CA097735), Familial Colorectal Neoplasia Collaborative Group (U01 CA074799) [USC], Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), Seattle Colorectal Cancer Family Registry (U01 CA074794) and University of Hawaii Colorectal Cancer Family Registry (U01 CA074806). A.K.W. is supported by the Picchi Brothers Foundation Cancer Council Victoria Cancer Research Scholarship, Australia. M.A.J. is an NHMRC Senior Research Fellow. J.L.H. is an NHMRC Australia Fellow. J.P.Y. is a Cancer Council Queensland Senior Research Fellow. ",

year = "2013",

month = may,

doi = "10.1016/j.ejca.2013.01.029",

language = "English (US)",

volume = "49",

pages = "1578--1587",

journal = "European Journal of Cancer",

issn = "0959-8049",